Discovery of novel cyclopentane carboxylic acids as potent and selective inhibitors of NaV1.7.

[Display omitted] • Proline analogs showed good potency on Na V 1.7 and selectivity against Na V 1.5 but possessed poor PK. • Cyclopentane carboxylic acid 31 provided an excellent balance between Na V 1.7 potency, selectivity over Na V 1.5, and PK properties. • An asymmetric synthesis of compound 31 was described. Discovery efforts leading to the identification of cyclopentane carboxylic acid 31 , a potent inhibitor of Na V 1.7 that showed high selectivity over Na V 1.5 and exhibited robust analgesic effects in an inherited erythromelalgia (IEM) transgenic mouse assay, are described herein. Key design elements that culminated in the discovery of 31 include exploration of proline substituents, replacement of the proline warhead with cyclopentane carboxylic acid, that led to significantly boosted Na V 1.7 potency, and replacement of the metabolically labile adamantane motif with the 2,6-dichlorobenzyl substituted piperidine system, that addressed metabolic instability and led to a significant improvement in PK. [ABSTRACT FROM AUTHOR]